The Women and Infants Transmission Study (WITS) is a national, multi-center, longitudinal observational cohort study of HIV-1 infected pregnant women and their infants that has been enrolling patients for the last decade. The overall goal of the study is to understand HIV-1 infection in pregnant women and in infants, children and adolescents, and the course, response, challenges, and side effects of antiretroviral therapy. This application is the WITS IV Leadership and Research Agenda application, which will be supported by six separate clinical site applications. The Leadership and Research Agenda will define the study aims, justification, study structure, and study approach for WITS IV. The Principle Investigator of the application will chair the WITS Executive Committee, the governing body of WITS. The Specific Aims for WITS IV include 1. To define the natural history of HIV-1 infection in infants, children, and adolescents in an era of antiretroviral therapy (ART); 2. To determine the immediate and late effects of exposure to ART in uninfected fetuses, infants, children, and adolescents; 3. To define the natural history of HIV-1 infected women enrolled during pregnancy in the era of ART; 4. To examine the relationships between adherence to ART medication, emergence of HIV-1 resistant to ART, and the clinical and treatment outcome in pediatric patients and their mothers; 5. To define the pathogenesis and natural history of HCV and HIV- 1/HCV co-infection in HIV-1 infected pregnant women, to identify a cohort of women with new HCV infection, and to examine the factors responsible for the transmission of HCV from mothers to their infants. This application will build on the studies done in WITS I-III to examine the changing landscape of HIV-1 infection in eras of increasing potency of ART. It will contribute to an in-depth understanding of the new era of perinatal HIV-1 infection and the consequence and challenges of therapy to prevent and treat the infection.